The present invention relates to certain resorcinol derivatives and their use as skin lightening agents.
The terms xe2x80x9clightening agentxe2x80x9d and xe2x80x9cdepigmentation agentxe2x80x9d are used interchangeably throughout this document.
Skin color in humans arises from a complex series of cellular processes that are carried out within a unique population of cells called melanocytes. Melanocytes are located in the lower part of the epidermis, and their function is to synthesize a pigment, melanin, which protects the body from the damaging effects of ultraviolet radiation.
When skin is exposed to ultraviolet radiation, such as that contained in sunlight, melanocytes increase their synthesis of melanin. Melanin is deposited in melanosomes, which are vesicles found within the cell. The melanosomes are extruded from the cell and carried to the surface of the skin by keratinocytes, which internalize the melanin-containing melanosomes. The end result is that the visible layers of the skin exhibit a brown color typically known as a xe2x80x9ctanxe2x80x9d. The darkness of the color observed in the skin is proportionate to the amount of melanin synthesized by melanocytes and transferred to the keratinocytes.
The mechanism by which skin pigmentation is formed, melanogenesis, is particularly complex and schematically involves the following main steps: Tyrosinexe2x86x92L-Dopaxe2x86x92Dopaquinonexe2x86x92Dopachromexe2x86x92Melanins. The first two reactions in this series are catalyzed by the enzyme tyrosinase. The activity of tyrosinase is promoted by the action of xcex1-melanocyte stimulating hormone or UV rays. It is well established that a substance has a depigmenting effect if it acts directly on the vitality of the epidermal melanocytes where melanogenesis normally occurs and/or if it interferes with one of the stages in melanin biosynthesis. The active compounds that are employed in the various methods and compositions of this invention inhibit tyrosinase and thus inhibit or decrease melanin biosynthesis.
There is a strong demand for agents that enable acquired deposition sites, such as spots or freckles, to be restored to a normal skin color. For this purpose, a variety of agents and methods have been developed and put on the market. Examples of such methods are (a) a method wherein vitamin C (L-ascorbic acid) having good reducing ability is administered orally in large amounts, (b) a method wherein glutathione is administered parenterally; (c) a method wherein a peroxide, such as hydrogen peroxide, zinc peroxide, sodium peroxide and the like, is administered: and (d) a method wherein vitamin C or cysteine is administered topically in the form of an ointment, cream, lotion or the like. Vitamin C has a problem with respect to stability and becomes so unstable in water-containing systems that they will cause changes in odor and color. Thiol compounds such as glutathione and cysteine do not exhibit a satisfactory depigmental effect since the development of the effect is very slow.
The substances in widest use at the present time as depigmentors are, in particular, hydroquinone and its derivatives, particularly its ethers such as hydroquinone monomethyl ether. These compounds, while effective, are known to produce side effects that can be dangerous. Hydroquinone, use of which is limited to a concentration of 2%, is both irritating and cytotoxic to the melanocyte.
U.S. Pat. No. 4,526,179 refers to certain hydroquinone fatty esters that have good activity and are less irritating and more stable than hydroquinone.
Japanese Patent Application No. 27909/86 refers to other hydroquinone derivatives that do not have the drawbacks of hydroquinone but that have relatively poor efficacy.
U.S. Pat. No. 5,449,518 refers to 2,5-dihydoxyphenyl carboxylic acid derivatives as skin depigmentation agents.
European Patent Application EP 341,664A1 refers to certain resorcinol derivatives as tyrosinase inhibitors and skin depigmentation agents.
PCT International Publication WO 99/15148 refers to certain resorcinol derivatives as tyrosinase inhibitors and skin depigmentation agents.
The use of topical depigmention agents that have good efficacy and are harmless is particularly desirable for treating the following: regional hyperpigmentation caused by melanocytic hyperactivity, such as idiopathic melasma occurring either during pregnancy (mask of pregnancy or chloasma) or secondary to estrogen-progesterone contraception; local hyperpigmentation caused by benign melanocytic hyperactivity and proliferation such as lentigo senilis or liver spots; accidental hyperpigmentation such as post-lesional photosensitization and scarring; and certain forms of leukoderma such as vitiligo where, if the injured skin cannot be repigmented, the residual zones of normal skin are depigmented to impart a homogeneous white color to the entire skin.
The resorcinol derivatives of formula I, which are defined below and used in the various methods and compositions of this invention, are useful in the treatment of the foregoing dermatological conditions as well as other dermatological conditions, some of which are referred to later in this document, for which the subject being treated desires, for medicinal or cosmetic purposes, to lighten or reduce the pigmentation of the skin affected by the condition.
The resorcinol derivatives of formula I are also useful for the treatment of inflammatory disorders such as psoriasis, dermatitis and acne, and for the treatment of dandruff.
The invention thus provides a compound of formula I: 
or a pharmaceutically acceptable salt thereof, wherein:
R is a (C3-C8)cycloalkyl or (C5-C8)cycloalkenyl ring substituted by xe2x80x94N(R1)CONR2R3 wherein R1 and R2 are independently selected from hydrogen, (C1-C6)alkyl, and, aryl(C1-C6)alkyl and R3 is hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, or aryl; xe2x80x94N(R4)COR5 wherein R4 is hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl-, or OH and R5 is (C7-C10)alkyl, aryl, aryl(C1-C6)alkyl-, xe2x80x94O-aryl, CF3, heterocycloalkyl, xe2x80x94(C1-C6)alkylheterocycloalkyl, xe2x80x94(C2-C7)alkenylheterocycloalkyl, heteroaryl, xe2x80x94(C1-C6)alkyl heteroaryl, xe2x80x94(C2-C7)alkenylheteroaryl, xe2x80x94(C2-C7)alkenylaryl, xe2x80x94(C2-C7)alkenylCOaryl, xe2x80x94(C1-C6)alkylN(R4)CO-aryl, xe2x80x94(C1-C6)alkylCO-aryl, xe2x80x94(C1-C6)alkylheterocycloalkyl, xe2x80x94(C1-C6)alkyl-X-aryl, (C2-C7)alkenyl, benzyhydryl, 5-hydroxyoxoindanyl, or tetrahydronaphthalenyl, wherein X is O, S, SO, SO2 or NR1; xe2x80x94N(R1)OCOaryl; xe2x95x90CHCO2R1; xe2x95x90CHCONR1R2; xe2x95x90CHCN; xe2x95x90NNHSO2R6 wherein R6 is aryl; xe2x80x94N(O)xe2x95x90CHR6; xe2x80x94OC(O)NR1R7 wherein R7 is aryl, aryl(C1-C6)alkyl-, xe2x80x94(C1-C6)alkyl-CO2(C1-C6)alkyl, xe2x80x94CO2(C1-C6)alkyl, xe2x80x94CO2aryl, xe2x80x94CO2aryl, or xe2x80x94CO2(C1-C6)alkylaryl; amino(C1-C6)alkylarylCO2xe2x80x94; or xe2x80x94OC(O)OR8 wherein R8 is (C1-C8)alkyl, aryl(C1-C6)alkyl, or aryl;
with the proviso that the cycloalkenyl ring is not aromatic.
In a preferred embodiment, R is substituted by xe2x80x94N(R1)CONR2R3.
In a further preferred embodiment, R is substituted by xe2x80x94N(R4)COR5.
In a further preferred embodiment, R is substituted by xe2x80x94N(R1)OCOaryl.
In a further preferred embodiment, R is substituted by xe2x95x90CHCO2R1.
In a further preferred embodiment, R is substituted by xe2x95x90CHCONR1R2.
In a further preferred embodiment, R is substituted by xe2x95x90CHCN.
In a further preferred embodiment, R is substituted by xe2x95x90NNHSO2R6.
In a further preferred embodiment, R is substituted by xe2x80x94N(O)xe2x95x90CHR6.
In a further preferred embodiment, R is substituted by xe2x80x94OC(O)NR1R7.
In a further preferred embodiment, R is substituted by amino(C1-C6)alkylarylCO2xe2x80x94.
In a further preferred embodiment, R is substituted by xe2x80x94OC(O)OR8.
The invention further provides a compound of formula I wherein R is a (C3-C8)cycloalkyl or (C5-C8)cycloalkenyl ring substituted by xe2x95x90CH2, or a pharmaceutically acceptable salt thereof; with the proviso that the cycloalkenyl ring is not aromatic.
In a preferred embodiment, R is a cycloalkyl ring, and preferably a cyclohexyl or cyclopentyl ring. Where R is a cyclohexyl or cyclohexenyl ring, the ring is preferably substituted at the 3- or 4-position, and more preferably at the 4-position. Where R is a cyclopentyl or cyclopentenyl ring, the ring is preferably substituted at the 3-position.
The invention further provides a compound of formula I wherein R is 3-cyclohexenyl, which is preferably unsubstituted, or a pharmaceutically acceptable salt thereof.
The invention further provides a compound of formula I, wherein R is a (C3-C8)cycloalkyl or (C5-C8)cycloalkenyl ring, wherein one of the carbon atoms of said cycloalkyl or cycloalkenyl rings is substituted by two groups such that the said groups are taken together with the carbon to which they are attached to form a ring of the formula: 
wherein X is O, S, SO, SO2 or NR1, wherein R1 is as defined above; Z is CH2, O, S, SO or SO2; m is 0-3; with the proviso that when m=0, then Z is CH2; and with the proviso that the cycloalkenyl ring is not aromatic; or a pharmaceutically acceptable salt thereof. In a preferred embodiment, m is 0. In a further preferred embodiment, m is 2. In a preferred embodiment, X and Z are both 0. In a further preferred embodiment, X and Z are both S. In a preferred embodiment, where R is a cyclohexyl or cyclohexenyl ring, the carbon of the cyclohexyl or cyclohexenyl ring which is substituted by the two groups is at the 3- or 4-position, and preferably at the 4-position, of the cyclohexyl or cyclohexenyl ring. In a further preferred embodiment, where R is a cyclopentyl or cyclopentenyl ring, the carbon of the cyclopentyl or cyclopentenyl ring which is substituted by the two groups is at the 3-position of the cyclopentyl or cyclopentenyl ring.
The invention further provides a compound of formula I, wherein R is a (C3-C8)cycloalkyl or (C1-C8)cycloalkenyl ring, wherein one of the carbon atoms of said cycloalkyl or cycloalkenyl rings is substituted by two groups such that the said groups are taken together with the carbon to which they are attached to form a ring of the formula: 
wherein X is O, S, SO, SO2 or NR1, wherein R1 is as defined above; and m is 0-3; and with the proviso that the cycloalkenyl ring is not aromatic; or a pharmaceutically acceptable salt thereof. In a preferred embodiment, m is 2. In a further preferred embodiment, X is 0. In a preferred embodiment, where R is a cyclohexyl or cyclohexenyl ring, the carbon of the cyclohexyl or cyclohexenyl ring which is substituted by the two groups is at the 3- or 4-position, and preferably at the 4-position, of the cyclohexyl or cyclohexenyl ring. In a further preferred embodiment, where R is a cyclopentyl or cyclopentenyl ring, the carbon of the cyclopentyl or cyclopentenyl ring which is substituted by the two groups is at the 3-position of the cyclopentyl or cyclopentenyl ring.
The invention further provides a compound selected from the group consisting of:
4-(1,4-Dioxaspiro[4.5]decyl)-1,3-benzenediol;
(xc2x1)-{4-[2,4-Dihydroxyphenyl]cyclohexylidene}acetic acid;
(xc2x1)-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]acetonitrile;
cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;
cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]benzamide;
trans-4-{4-[(Z)benzylidene(oxido)amino]cyclohexyl}-1,3-benzenediol;
trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;
syn-8-(2,4-Dihydroxyphenyl)-1-oxaspiro[4.5]decan-2-one;
cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-Nxe2x80x2-phenylurea;
trans-Phenyl-4-(2,4-dihydroxyphenyl)cyclohexylcarbamate;
cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-Nxe2x80x2-ethylurea;
cis-N-Benzyl-N[4-(2,4-dihydroxyphenyl)cyclohexyl]propanamide;
trans-4-(2,4-Dihydroxyphenyl)cyclohexylphenylcarbamate;
trans-Ethyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;
trans-4-(2,4-Dihydroxyphenyl)cyclohexyl benzylcarbamate;
trans-4-(2,4-Dihydroxyphenyl)cyclohexyl ethyl carbonate;
trans-Methyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;
trans-4-(2,4-Dihydroxyphenyl)cyclohexyl methyl imidodicarbonate;
cis/trans-4-(1-Oxaspiro[2.5]oct-6-yl)-1,3-benzenediol;
4-(4-Methylenecyclohexyl)-1,3-benzenediol;
4-(3-Cyclohexen-1-yl)-1,3-benzenediol;
trans-4-(2,4-Dihydroxyphenyl)cyclohexyl (2R)-2-amino-3-phenylpropanoate;
Benzyl [4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate;
4-(1,4-Dithiaspiro[4.5]dec-8-yl)-1,3-benzenediol;
Nxe2x80x2-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]4-methylbenzenesulfonohydrazide;
trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-nitrobenzamide;
trans-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-Nxe2x80x2-phenylurea;
trans-N-[4-(dihydroxyphenyl)cyclohexyl]-2,2,2-trifluoroacetamide;
cis-3-cyano-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;
cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy (trifluoromethyl)benzamide;
cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxymethoxybenzamide;
(xc2x1)-Methyl[4-(2,4-dihydroxyphenyl)cyclohexylidene] acetate;
and a pharmaceutically acceptable salt thereof.
The present invention further provides a pharmaceutical composition for lightening skin or reducing the pigmentation of skin in a human, comprising a pharmaceutically acceptable carrier, and a skin-lightening or pigmentation-reducing effective amount of a compound of formula I: 
or a pharmaceutically acceptable salt thereof, wherein:
R is a (C3-C8)cycloalkyl or (C5-C8)cycloalkenyl ring substituted by xe2x80x94N(R1)CONR2R3 wherein R1 and R2 are independently selected from hydrogen, (C1-C6)alkyl, and aryl(C1-C6)alkyl and R3 is hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, or aryl; xe2x80x94N(R4)COR5 wherein R4 is hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl-, or OH and R5 is (C7-C10)alkyl, aryl, aryl(C1-C6)alkyl-, xe2x80x94O-aryl, CF3, heterocycloalkyl, xe2x80x94(C1-C6)alkylheterocycloalkyl, xe2x80x94(C2-C7)alkenylheterocycloalkyl, heteroaryl, xe2x80x94(C1-C6)alkyl heteroaryl, xe2x80x94(C2-C7)alkenylheteroaryl, xe2x80x94(C2-C7)alkenylaryl, xe2x80x94(C2-C7)alkenylCOaryl, xe2x80x94(C1-C6)alkylN(R4)CO-aryl, xe2x80x94(C1-C6)alkylCO-aryl, xe2x80x94(C1-C6)alkylhydroxyaryl, xe2x80x94(C1-C6)alkyl-X-aryl, (C2-C7)alkenyl, benzyhydryl, 5-hydroxyoxoindanyl, or tetrahydronaphthalenyl, wherein X is O, S, SO, SO2 or NR1; xe2x80x94N(R1)OCOaryl; xe2x95x90CHCO2R1; xe2x95x90CHCONR1R2; xe2x95x90CHCN; xe2x95x90NNHSO2R6 wherein R6 is aryl; xe2x80x94N(O)xe2x95x90CHR6; xe2x80x94OC(O)NR1R7 wherein R7 is aryl, aryl(C1-C6)alkyl-, xe2x80x94(C1-C6)alkyl, CO2(C1-C6)alkyl, xe2x80x94CO2(C2aryl, or xe2x80x94CO2(C1-C5)alkylaryl; amino(C1-C5)alkylarylCO2xe2x80x94; or xe2x80x94OC(O)OR8 wherein R1 is (C1-C6)alkyl, aryl(C1-C6)alkyl, or aryl;
with the proviso that the cycloalkenyl ring is not aromatic.
In a preferred embodiment, R is substituted by xe2x80x94N(R1)CONR2R3.
In a further preferred embodiment, R is substituted by xe2x80x94N(R4)COR5.
In a further preferred embodiment, R is substituted by xe2x80x94N(R1)OCOaryl.
In a further preferred embodiment, R is substituted by xe2x95x90CHCO2R1.
In a further preferred embodiment, R is substituted by xe2x95x90CHCONR1R2.
In a further preferred embodiment, R is substituted by xe2x95x90CHCN.
In a further preferred embodiment, R is substituted by xe2x95x90NNHSO2R6.
In a further preferred embodiment, R is substituted by xe2x80x94N(O)xe2x95x90CHR6.
In a further preferred embodiment, R is substituted by xe2x80x94OC(O)NR R7.
In a further preferred embodiment, R is substituted by amino(C1-C6)alkylarylCO2xe2x80x94.
In a further preferred embodiment, R is substituted by xe2x80x94OC(O)OR8.
The invention further provides a pharmaceutical composition for lightening skin or reducing the pigmentation of skin in a human, comprising a pharmaceutically acceptable carrier, and a skin-lightening or pigmentation-reducing effective amount of a compound of formula I wherein R is a (C3-C8)cycloalkyl or (C5-C8)cycloalkenyl ring substituted by xe2x95x90CH2, with the proviso that the cycloalkenyl ring is not aromatic, or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, R is a cycloalkyl ring, and preferably a cyclohexyl or cyclopentyl ring. Where R is a cyclohexyl or cyclohexenyl ring, the ring is preferably substituted at the 3- or 4-position, and more preferably at the 4-position. Where R is a cyclopentyl or cyclopentenyl ring, the ring is preferably substituted at the 3-position.
The invention further provides a pharmaceutical composition for lightening skin or reducing the pigmentation of skin in a human, comprising a pharmaceutically acceptable carrier, and a skin-lightening or pigmentation-reducing effective amount of a compound of formula I wherein R is 3-cyclohexenyl, which is preferably unsubstituted, or a pharmaceutically acceptable salt thereof.
The invention further provides a pharmaceutical composition for lightening skin or reducing the pigmentation of skin in a human, comprising a pharmaceutically acceptable carrier, and a skin-lightening or pigmentation-reducing effective amount of a compound of formula I, wherein R is a (C3-C8)cycloalkyl or (C5-C8)cycloalkenyl ring, wherein one of the carbon atoms of said cycloalkyl or cycloalkenyl rings is substituted by two groups such that the said groups are taken together with the carbon to which they are attached to form a ring of the formula: 
wherein X is O, S, SO, SO2 or NR1, wherein R1 is as defined above; Z is CH2, O, S, SO or SO2; m is 0-3; with the proviso that when m=0, then Z is CH2; and with the proviso that the cycloalkenyl ring is not aromatic; or a pharmaceutically acceptable salt thereof. In a preferred embodiment, m is 0. In a further preferred embodiment, m is 2. In a preferred embodiment, X and Z are both O. In a further preferred embodiment, X and Z are both S.
The invention further provides a pharmaceutical composition for lightening skin or reducing the pigmentation of skin in a human, comprising a pharmaceutically acceptable carrier, and a skin-lightening or pigmentation-reducing effective amount of a compound of formula I, wherein R is a (C3-C8)cycloalkyl or (C5-C8)cycloalkenyl ring, wherein one of the carbon atoms of said cycloalkyl or cycloalkenyl rings is substituted by two groups such that the said groups are taken together with the carbon to which they are attached to form a ring of the formula: 
wherein X is O, S, SO, SO2 or NR1, wherein R1 is as defined above; and m is 0-3; and with the proviso that the cycloalkenyl ring is not aromatic; or a pharmaceutically acceptable salt thereof. In a preferred embodiment, m is 2. In a further preferred embodiment, X is O.
In a preferred embodiment, the pharmaceutical composition of the present invention is adapted for topical application.
The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a skin-lightening or pigmentation-reducing effective amount of a compound selected from the group consisting of:
4-(1,4-Dioxaspiro[4.5]dec-8-yl)-1,3-benzenediol;
(xc2x1)-{4-[2,4-Dihydroxyphenyl]cyclohexylidene}acetic acid;
(xc2x1)-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]acetonitrile;
cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;
cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]benzamide;
trans-4-{4-[(Z)benzylidene(oxido)amino]cyclohexyl}-1,3-benzenediol;
trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;
syn-8-(2,4-Dihydroxyphenyl)-1-oxaspiro[4.5]decan-2-one;
cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-Nxe2x80x2-phenylurea;
trans-Phenyl-4-(2,4-dihydroxyphenyl)cyclohexylcarbamate;
cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-Nxe2x80x2-ethylurea;
cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]propanamide;
trans-4-(2,4-Dihydroxyphenyl)cyclohexylphenylcarbamate;
trans-Ethyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;
trans-4-(2,4-Dihydroxyphenyl)cyclohexyl benzylcarbamate;
trans-4-(2,4-Dihydroxyphenyl)cyclohexyl ethyl carbonate;
trans-Methyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;
trans-4-(2,4-Dihydroxyphenyl)cyclohexyl methyl imidodicarbonate;
cis/trans-4-(1-Oxaspiro[2.5]oct-6-yl)-1,3-benzenediol;
4-(4-Methylenecyclohexyl)-1,3-benzenediol;
4-(3-Cyclohexen-1-yl)-1,3-benzenediol;
trans-4-(2,4-Dihydroxyphenyl)cyclohexyl (2R)-2-amino-3-phenylpropanoate;
Benzyl [4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate;
4-(1,4-Dithiaspiro[4.5]dec-8-yl)-1,3-benzenediol;
Nxe2x80x2-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]-4-methylbenzenesulfonohydrazide;
trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-nitrobenzamide;
trans-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-Nxe2x80x2-phenylurea;
trans-N-[4-(dihydroxyphenyl)cyclohexyl]-2,2,2-trifluoroacetamide;
cis-3-cyano-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;
cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy-4-(trifluoromethyl)benzamide;
cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy-4-methoxybenzamide;
(xc2x1)-Methyl [4-(2,4-dihydroxyphenyl)cyclohexylidene] acetate;
and a pharmaceutically acceptable salt thereof.
The invention further provides a cosmetic composition comprising a cosmetically acceptable topical carrier in combination with any one or more of the compounds of formula I, or a cosmetically acceptable salt thereof.
The present invention further provides a method of lightening skin in a human, comprising administering to said human a skin-lightening or pigmentation-reducing effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the present invention provides a method of lightening skin in a human in need of said treatment, comprising administering to said human a skin-lightening effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of inhibiting tyrosinase in a human, comprising administering to said human a tyrosinase-inhibiting effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the present invention provides a method of inhibiting tyrosinase in a human in need of said treatment, comprising administering to said human a tyrosinase-inhibiting effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The present invention further provides a topical or transdermal pharmaceutical composition for the treatment of an inflammatory disorder or condition such as psoriasis, dermatitis or acne, or for the treatment of dandruff, in a human in need of said treatment, comprising a pharmaceutically acceptable carrier, and an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, which amount is effective in treating such disorder or condition.
The present invention further provides a method of treating an inflammatory disorder, such as psoriasis, dermatitis or acne, or a method of treating dandruff, in a human in need of said treatment, comprising administering to said human an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, which amount is effective in treating such disorder or condition.
The present invention further provides a kit, comprising a container comprising one or more specific compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions, of the present invention that lighten skin. The kit may further comprise printed instructions as a label or package insert directing the use of the enclosed compound or composition to lighten skin pigmentation.
As used herein, the terms xe2x80x9ctreatxe2x80x9d and xe2x80x9ctreatingxe2x80x9d, and the like, refer to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. Any substituents or functional groups on the alkyl group, as indicated herein, can be substituted anywhere on the alkyl group.
The term xe2x80x9calkenylxe2x80x9d, as used herein, unless otherwise indicated, includes unsaturated hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof, with one or more, and preferably one or two, double bonds. Any substituents or functional groups on the alkyl group, as indicated herein, can be substituted anywhere on the alkenyl group.
The term xe2x80x9carylxe2x80x9d, as used herein, refers to a (C5-C10) aryl, preferably phenyl or naphthyl, optionally substituted with one or more substituents, and preferably one or two substituents, independently selected from halogen, OH, (C1-C6)alkyl, amino, (C1-C6)alkylamino-, di-((C1-C6)alkyl))amino-, xe2x80x94NR1COR1 wherein each R1 is independently selected from the group described above, nitro, cyano, xe2x80x94Xxe2x80x94(C1-C6)alkyl, xe2x80x94Xxe2x80x94(C1-C6)alkylaryl, xe2x80x94X-aryl, where X is defined above, trifluoromethyl, xe2x80x94OCF3, xe2x80x94CO(C1-C6)alkyl, xe2x80x94COaryl, xe2x80x94COCF3, xe2x80x94CONR12, (C2-C7)alkenyl, aryl, (C3-C9)heterocycloalkyl, and (C5-C10)heteroaryl. Any substituents or functional groups on the aryl group, as indicated herein, can be substituted anywhere on the aryl group.
The term xe2x80x9cone or more substituentsxe2x80x9d, as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites.
The term xe2x80x9chalogenxe2x80x9d as used herein, unless otherwise indicated, refers to chlorine, fluorine, bromine and iodine.
The term xe2x80x9cheteroarylxe2x80x9d, as used herein, refers to a (C2-C10)heteroaryl, more preferably a (C5-C10)heteroaryl, and more preferably a 5- or 6-membered heteroaryl, containing one to five N, O or S atoms. In a preferred embodiment, the heteroaryl is selected from furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, cinnolinyl, pteridinyl, purinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, 6,7-dihydro-5H-[1]pyridinyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolinyl, quinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl, 4-oxo-1,4-dihydro[1,8]naphthyridin-3-yl, benzo[1,3]dioxol-5-yl, and 4-oxo-6,7-dihydro-5H-benzofuryl. One of ordinary skill in the art will understand that the connection of said (C2-C9)heteroaryl ring can be through a carbon atom or through a nitrogen heteroatom where possible.
The heteroaryl may be optionally substituted with one or more substituents, preferably one or two substituents, independently selected from halogen, OH, (C1-C6)alkyl, xe2x80x94(C1-C6)alkoxy, amino, (C1-C6)alkylamino-, di-((C1-C6)alkyl))amino-, xe2x80x94NR1COR1 wherein each R1 is independently selected from the group described above, nitro, cyano, xe2x80x94Xxe2x80x94(C1-C6)alkyl, xe2x80x94X-aryl, where X is defined above, trifluoromethyl, xe2x80x94OCF3, xe2x80x94S(O)p(C1-C6)alkyl where p is 0, 1 or 2, xe2x80x94COaryl, xe2x80x94COCF3, xe2x80x94CO(C1-C6)alkyl, xe2x80x94(C1-C6)alkylOH, xe2x80x94COOR1, xe2x80x94(C1-C6)alkylCOOR1,xe2x80x94CONR12, (C2-C7)alkenyl, xe2x80x94CONH(CHR1)qCO2R1 where q is 1 or 2, xe2x80x94CONR1N(R1)2, aryl, xe2x80x94(C1-C6)alkylaryl, (C3-C9)heterocycloalkyl, (C5-C10)heteroaryl, and xe2x80x94(C1-C6)alkyl(C2-C9)heteroaryl. Any substituents or functional groups on the heteroaryl group, as indicated herein, can be substituted anywhere on the heteroaryl group.
The term xe2x80x9cheterocycloalkylxe2x80x9d, as used herein, refers to a (C2-C10)heterocycloalkyl, more preferably a (C5-C10)heterocycloalkyl, and more preferably a 5- or 6-membered heterocycloalkyl, containing from one to five N, O or S atoms. In a preferred embodiment, the heterocycloalkyl group is selected from pyrrolidinyl, dihydropyrrolindinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, pyrazolidinyl, piperidinyl, thiomorpholinyl, tetrahydrothiazinyl, thiadiazinyl, -tetrahydrothiadiazinyl, morpholinyl, tetrahydrodiazinyl, tetrahydroazepinyl, piperazinyl, chromanyl, oxopyrrolidinyl, 1,3-dioxo-1,3-dihydroisoindolyl, 6-oxo-1,4,5,6,-tetrahydropyridazin-4-yl, 2,3-dihydrobenzo[1,4]dioxin-2-yl, 2-oxo-2H-chromen-5-yl, benzo[1,3]dioxol-5-yl, and 3-oxo-3H-isobenzofuran-1-ylidinemethyl. One of ordinary skill in the art will understand that the connection of said heterocycloalkyl ring can be through a carbon atom or through a nitrogen heteroatom where possible.
The heterocycloalkyl may be optionally substituted with one or more substituents, preferably one or two substituents, independently selected from halogen, OH, xe2x80x94(C1-C6)alkyl, xe2x80x94(C1-C6)alkoxy, xe2x80x94S(O)p(C1-C6)alkyl where p is 0, 1 or 2, amino, xe2x95x90O, (C1-C6)alkylamino, di-((C1-C6)alkyl))amino, NR1COR1 wherein each R1 is independently selected from the group described above, xe2x80x94COOR1, xe2x80x94(C1-C6)alkylCOOR1, xe2x80x94CONH(CHR1)qCO2R1 where q is 1 or 2, xe2x80x94CONR1N(R1)2, xe2x80x94(C1-C6)alkylOH, xe2x80x94CO(C1-C6)alkyl, nitro, cyano, xe2x80x94Xxe2x80x94(C1-C6)alkyl, xe2x80x94X-aryl, where X is defined above, trifluoromethyl, xe2x80x94OCF3, xe2x80x94COaryl, xe2x80x94COCF3, xe2x80x94CO(C1-C6)alkyl, xe2x80x94CONR12, (C2-C7)alkenyl, (C1-C6)alkylaryl, aryl, (C3-C9)heterocycloalkyl, (C5-C10)heteroaryl, and xe2x80x94CO2(C1-C6)alkyl. Any substituents or functional groups on the aryl group, as indicated herein, can be substituted anywhere on the aryl group. In a preferred embodiment, the heterocycloalkyl group is substituted with one or more substituents, preferably one or two substituents, independently selected from halogen, OH, xe2x80x94(C1-C6)alkyl, amino, and trifluoromethyl. Any substituents or functional groups on the heterocycloalkyl group, as indicated herein, can be substituted anywhere on the aryl group.
Compounds of formula I may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms. This invention relates to all optical isomers, stereoisomers and tautomers of the compounds of formula I, II and III, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment defined above that contain or employ them, respectively.
Formula I, as defined above, also includes compounds identical to those depicted but for the fact that one or more hydrogen, carbon or other atoms are replaced by isotopes thereof. Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
The present invention also relates to the pharmaceutically acceptable acid addition and base salts of any of the aforementioned compounds of formula I. The acids that are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate p-toluenesulfonate and pamoate (i.e., 1,1-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
As used herein, a xe2x80x9cskin-lightening or pigmentation reducing amount of a compound of formula Ixe2x80x9d, and the like, means an amount or concentration of the compound capable of detectably lightening skin or reducing pigmentation in a human, as determined by any standard assay. The active compound is typically administered in a pharmaceutical composition and for a standard course of treatment that produces the desired result of skin depigmentation.
As used herein, a xe2x80x9ctyrosinase-inhibiting effective amount of a compound of formula Ixe2x80x9d, and the like, means an amount or concentration of the compound capable of detectably inhibiting tyrosinase activity in a human, as determined by any standard assay, such as those described below.
As used herein, an xe2x80x9camount of a compound of formula I capable of treating an inflammatory disorder such as psoriasis, dermatitis or acne, or treating dandruffxe2x80x9d, and the like, means an amount or concentration of the compound capable of detectably ameliorating, reducing, eliminating, slowing, or preventing the progression of, any symptom or condition associated with or caused by such disorder or condition, in a human, as determined by any standard assay.